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Project 1 - Exploiting Metabolic Vulnerabilities

项目 1 - 利用代谢漏洞

基本信息

批准号：
10242862
负责人：
CHRISTOPHER M SASSETTI
金额：
$ 64.76万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10242862
关键词：
Acyl Coenzyme A Amino Acids Animal Model Anti-Bacterial Agents Bacteria Binding Biochemical Biology Carbon Cell Wall Cells Chemicals Complex Critical Pathways Crystallization Development Drug Design Drug Targeting Ensure Enzymes Genetic Genetic Screening Genus Mycobacterium Goals Growth Heme In Vitro Infection Lipids Malate Dehydrogenase Metabolic Metabolic Pathway Metabolism Methods Multienzyme Complexes Mycobacterium tuberculosis Orthologous Gene Pathway interactions Phosphoenolpyruvate Carboxylase Physiological Program Development Prokaryotic Cells Proteins Pyruvate Kinase Resources Role Source Specificity Structure Variant base chemical genetics cofactor design drug development high throughput screening improved inhibitor/antagonist insight interdisciplinary approach multidisciplinary mycobacterial novel pathogen programs protein complex protein function protein structure small molecule small molecule inhibitor structural biology tool

项目摘要

Project Summary – Project 1 - Exploiting metabolic vulnerabilities Central metabolic pathways are critical for bacterial viability and represent a rich source of potential drug targets. However, these enzymes have been under-exploited by anti-bacterial drug development programs for two basic reasons. Firstly, these complex pathways perform diverse roles under different growth states, leaving their importance during infection unclear. In addition, homologous mammalian enzymes often exist, necessitating the design of specific inhibitors. To overcome these complications and exploit this rich source of potential drug targets, we use a combination of genetics and chemical biology to identify druggable metabolic enzymes that are essential in relevant host microenvironments, and employ structural biology to aid in the development of specific inhibitors. These studies have defined target-inhibitor pairs in a broad range of metabolic pathways and regulators. For example, central carbon metabolic enzymes critical for bacterial survival in animal models, such as phophoenolpyruvate carboxykinase (PEPCK), pyruvate kinase (PK), and malate dehydrogenase, have been subjected to structure-guided inhibitor design. Similar approaches have been applied to critical components of lipid anabolic pathways, such as PKS13 and components of acyl-CoA carboxylase complexes, enzymes critical for amino acid and cofactor synthesis, and heme metabolism. These studies have identified potent and specific small molecule inhibitors, revealed novel protein complexes and elucidated the physiological functions of these enzymes in the bacterium.

项目摘要-项目1 -利用代谢漏洞中心代谢途径对细菌的生存能力至关重要，并代表了潜在药物的丰富来源目标的然而，这些酶在抗菌药物开发中未得到充分利用有两个基本原因。首先，这些复杂的途径在不同的条件下发挥不同的作用。生长状态，使其在感染期间的重要性不清楚。此外，同源哺乳动物酶通常存在，需要设计特定的抑制剂。为了克服这些并发症并利用这一丰富的潜在药物靶点来源，我们使用遗传学和化学的组合，生物学鉴定在相关宿主微环境中必不可少的可药用代谢酶，并利用结构生物学来帮助开发特异性抑制剂。这些研究定义了靶向抑制剂对广泛的代谢途径和调节剂。例如，中心碳动物模型中对细菌存活至关重要的代谢酶，如磷酸烯醇丙酮酸羧激酶（PEPCK）、丙酮酸激酶（PK）和苹果酸脱氢酶，已经经历了结构导向抑制剂设计。类似的方法已应用于脂质的关键成分合成代谢途径，如PKS 13和酰基辅酶A羧化酶复合物的组分，酶对氨基酸和辅因子合成以及血红素代谢至关重要。这些研究已经发现，和特定的小分子抑制剂，揭示了新的蛋白质复合物，并阐明了生理这些酶在细菌中的功能。